Parental imprinting of the X chromosome: effects on neurodegeneration

摘要： MS是一种涉及免疫系统和中枢神经系统（CNS）的复杂疾病。 女性比男性更容易患MS，女性的免疫反应更强。 然而，女性并没有表现出更快的残疾进展。相反，作为男性是一个风险因素， 进展显然，免疫反应和神经退行性变必须独立研究， 疾病的性别差异。 该提案将侧重于不扩散核武器系统。辐射骨髓嵌合体是一种成熟的工具， 独立于其他组织操纵免疫系统。我们将用骨髓嵌合体 研究免疫系统中没有性别差异的中枢神经系统的性别差异。性别差异 通过使用不同性别的小鼠， 染色体，同时具有相同的性腺类型。通过改变嵌合体的性染色体 在共同的免疫系统中，可以确定性染色体在中枢神经系统反应中的作用， 实验性自身免疫性脑脊髓炎（EAE）期间的损伤，最广泛使用的MS模型。 具体的目标将解决我们的总体假设，即母系遗传的X染色体基因（S） 导致男性比女性更容易神经退化，因为这些基因表达得更多， 男性的XmY比女性的XmXp要多。在目标#1中，我们将确定性别差异 染色体影响EAE期间CNS中的基因表达。在目标#2中，我们将确定 与父方印记的X染色体影响DNA甲基化和染色质可及性的基因 在中枢神经系统中的作用在目标3中，我们将使用中枢神经系统细胞特异性基因表达方法（RiboTag）来 确定EAE期间CNS中哪些细胞的性染色体基因不同。目标#4。我们将确定 EAE期间CNS细胞中差异表达的性染色体基因的功能意义。 上述目标将共同确定导致更差的临床和免疫缺陷的性染色体基因。 神经病理性疾病这些发现将揭示新的目标，最终目标是找到治疗方法。 阻止或减缓MS和其他潜在神经系统疾病的神经变性和残疾进展。

Abstract: MS is a complex disease involving both the immune system and the central nervous system (CNS). Females are more susceptible to MS than males, and immune responses are more robust in females. However, females do not demonstrate faster disability progression. Instead, being male is a risk factor for progression. Clearly immune responses and neurodegeneration must be studied independently with respect to sex differences in disease. This proposal will focus on the CNS. Irradiation bone marrow chimeras are a well established tool to manipulate the immune system independently from other tissues. We will use bone marrow chimeras to investigate sex differences in the CNS where there is no sex difference in the immune system. Sex differences will focus on a potential role for sex chromosomes, rather than sex hormones, by using mice that differ in sex chromosomes while having the same gonadal type. By varying sex chromosomes in chimeras reconstituted with a common immune system, one can ascertain the role of sex chromosomes on the CNS response to injury during experimental autoimmune encephalomyelitis (EAE), the most widely used model of MS. Four specific aims will address our overarching hypothesis that maternally inherited X chromosome gene(s) lead to more neurodegeneration in males compared to females, since these genes are expressed more in males who are XmY than females who are XmXp. In aim #1, we will determine how a difference in sex chromosomes affects gene expression in the CNS during EAE. In aim #2, we will determine how maternal versus paternal imprinting of the X chromosome affects DNA methylation and chromatin accessibility of genes in the CNS during EAE. In aim #3, we will use a CNS cell specific gene expression approach (RiboTag) to identify which sex chromosome genes differ in which cell in the CNS during EAE. In aim #4. We will determine the functional significance of sex chromosome genes that are differentially expressed in CNS cells during EAE. Together the above aims will identify sex chromosome gene(s) that lead to worse clinical and neuropathological disease. These findings will reveal new targets with the ultimate goal of finding a treatment to halt or slow neurodegeneration and disability progression in MS and potentially other neurological diseases.